Protection of Pancreatic β-Cells by Group VIA Phospholipase A2-Mediated Repair of Mitochondrial Membrane Peroxidation
Open Access
- 12 March 2010
- journal article
- other
- Published by The Endocrine Society in Endocrinology
- Vol. 151 (7), 3038-3048
- https://doi.org/10.1210/en.2010-0016
Abstract
Mitochondrial production of reactive oxygen species and oxidation of cardiolipin are key events in initiating apoptosis. We reported that group VIA Ca2+-independent phospholipase A2 (iPLA2β) localizes in and protects β-cell mitochondria from oxidative damage during staurosporine-induced apoptosis. Here, we used iPLA2β-null (iPLA2β−/−) mice to investigate the role of iPLA2β in the repair of mitochondrial membranes. We show that islets isolated from iPLA2β−/− mice are more sensitive to staurosporine-induced apoptosis than those from wild-type littermates and that 2 wk of daily ip administration of staurosporine to iPLA2β−/− mice impairs both the animals’ glucose tolerance and glucose-stimulated insulin secretion by their pancreatic islets. Moreover, the iPLA2β inhibitor bromoenol lactone caused mitochondrial membrane peroxidation and cytochrome c release, and these effects were reversed by N-acetyl cysteine. The mitochondrial antioxidant N-t-butyl hydroxylamine blocked staurosporine-induced cytochrome c release and caspase-3 activation in iPLA2β−/− islets. Furthermore, the collapse of mitochondrial membrane potential in INS-1 insulinoma cells caused by high glucose and fatty acid levels was attenuated by overexpressing iPLA2β. Interestingly, iPLA2β was expressed only at low levels in islet β-cells from obesity- and diabetes-prone db/db mice. These findings support the hypothesis that iPLA2β is important in repairing oxidized mitochondrial membrane components (e.g. cardiolipin) and that this prevents cytochrome c release in response to stimuli that otherwise induce apoptosis. The low iPLA2β expression level in db/db mouse β-cells may render them vulnerable to injury by reactive oxygen species.Keywords
Funding Information
- National Institutes of Health (DK074805)
- Iacocca Family Foundation
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